Compounds which inhibit HDACs catalyze the removing of the acetyl group from lysine residues in the N-terminal tails of nucleosomal core histones resulting in a more compact chromatin structure, a configuration that is generally associated with repression of transcription (Davie J. R. et al., J. Cell. Biochem. suppl. 30-31, 203-213, 1998). HDACs are involved in cell-cycle progression and differentiation, and their deregulation is associated with several cancers. HDAC inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have anti-tumour effects, as they can inhibit cell growth, induce terminal differentiation and prevent the formation of tumours in mice models, and they are effective in the treatment of promyelocytic leukaemia (Finnin M. S. et al., Nature, 401, 188-193, 1999 and references therein). Trichostatin A has also been reported to be useful in the treatment of fibrosis, e.g. liver fibrosis and liver chirrhosis. (European Patent Application EP 0 827 742, published 11 Mar., 1998). Recent evidences have been found than certain HDAC inhibitor (e.g. SAHA) can cross the blood brain barrier to inhibit HDAC activity causing the accumulation of acetylated histones in the brain (WO 03032921). SAHA has been shown to dramatically improve the motor impairment in R6/2 mice, clearly validating the pursuit of this class of compounds as Huntington's disease (HD) therapeutics. More generally HDAC inhibitors could be useful for treating diseases of the central nervous system (CNS) in particular neurodegenerative diseases inherited such as polyglutamine expansion diseases (e.g. HD, Steffan J. et al., Nature, 413, 739-744, 2001 and Hockly E. et al., PNAS 100(4), 2041-2046, 2003).
Nine human HDAC have been characterized and two inferred; these members fall into two related classes (Class I and Class II). HDAC 1, 2, 3 and 8 belong to the human Class I that has homology to the yeast protein rpd3. They are located in the nucleus, and are found in complexes associated with transcriptional corepressors. The class II enzyme has six representatives so far (HDAC 4-6 and 7-10) and they all show homology to the related yeast enzyme HDA1 and are found in both the nucleus and cytoplasm. Both class I and II HDACs are inhibited by SAHA and related hydroxamic acid-based HDAC inhibitors. Class III HDACs form a structurally distant class of NAD-dependent enzymes that are related to the yeast SIR2 proteins and are not inhibited by hydroxamic acid-based HDAC inhibitors (Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 18, 11700-11705, Sep. 3, 2002)
A very few of small molecules are known that selectively target either the two classes (class I or II) or individual members (HDAC1-10) of this family (Stenson S. et al., Org. Lett., 26(3), 4239-4242, 2001).
Some of the compounds of the present invention have also been designed to be able to cross the blood brain barrier as they have low molecular weight and a calculated polar surface area (PSA)<90 A2.
There is still a need for high enzymatic activity and more selective HDAC inhibitors with little or no side effects.
The novel compounds of the present invention solve the above-described problem. The compounds differ from the prior art in structure. The compounds of the present invention show good in vitro histone deacetylase inhibiting enzymatic activity.
Accordingly, one aspect of the invention is to provide a compound having a general formula (I):
wherein:    R is —C(O)NR7R8, —(CXY)tC(O)NR7R8, —C(O)C(O)NHMe, —(C═C)C(O) NR8R9, —C(O)CF3, or another Zn-chelating-group, with the proviso that R is not an acidic group or an ester derivative, —COOR9 or salt thereof, R7 is a group of formula —OH, —OR9, 2-aminophenyl and R8 is selected from hydrogen, C1-6alkyl; R9 is independently selected from hydrogen or C1-6alkyl; t is 1, 2 or 3 (preferably 1), X and Y, which are identical or different, represent an hydrogen or halogen atom (preferably F),    X1 represents a carbon, oxygen, nitrogen or sulphur atom,    R1 and R2 represent independently or form together:            a C1-6alkyl group, in particular methyl or ethyl groups, when X1 is an atom of carbon,        nothing, when X1 is an atom of oxygen or an atom of sulphur,        one or two atoms of oxygen, when X1 is an atom of sulphur (the case of a sulfoxide —SO— or a sulphone —SO2—), or        one atom of hydrogen, an alkyl, aryl or aralkyl group, when X1 is an atom of nitrogen (the case of an amino —NH, -an N-alkyl, N-aryl or N-aralkyl group);            X2 and X3, which are identical or different, represent CH, an atom of oxygen or an atom of nitrogen, or X2═X3 may be a single atom of sulphur, oxygen or nitrogen, or in the case where X2 is an atom of oxygen and X3 an atom of nitrogen, C1 and X4 represent a single one and same carbon atom, so that the ring carrying X2 and X3 can be an isoxazole ring,    X4 can be CH or a nitrogen atom,    R4 and R5, which are identical or different, represent a hydrogen atom, a halogen atom, more particularly a fluorine atom, a C1-6alkyl group, a group of formula —OH, —NH2, —NHR6, —OR6, —SR6, —(CF2)nCF3, where n is an integer from 0 to 10, and whenever possible their salts with physiologically tolerated acids,    R6 represents a hydrogen atom, a C1-6alkyl group, a fluoroalkyl group having from 1 to 6 carbons atoms and from 3 to 7 fluorine atoms, an aryl group or an aralkyl group;    R3 has the same definition as R4 and R5;    L is a linker and represents a bivalent radical either linear or cyclic, either saturated or unsaturated, more particularly L represents a bivalent radical derived from an alkane, alkene, alkyne or, aromatic or not, cyclic containing hydrocarbon group having from 1 to 12 carbon atoms, another bivalent radical of the following formula —O—, —CO—, —CO—NH—, —NH—CO—, —NH—CO—NH—, —CF2—CO—NH—, —C(XY)—CO—NH—CH2—, —NH—CO—CO—NH—, —NH—CO—CO—NH—CH2—, —SO2NH—, —NHSO2—, —SO2NCH3—, —NCH3SO2—, —NR6—, —C(═NOH)—, or a mixture thereof; R6 being as defined above, optionally the bivalent radical is substituted, in particular by at least one C1-6alkyl group; X and Y, which are identical or different, represent an hydrogen or halogen atom (preferably F);its tautomers, optical and geometrical isomers, racemates, salts, hydrates and mixtures thereof.
The compounds of the present invention may have one or more asymmetric centers and it is intended that stereoisomers (optical isomers), as separated, pure or partially purified stereoisomers or racemic mixtures thereof are included in the scope of the invention.
The present invention more particularly deals with the compounds of the present invention for use as a medicine.
The present invention also relates to pharmaceutical compositions comprising at least one compound as defined above in a pharmaceutically acceptable support, optionally in association with another active agent.
The pharmaceutical composition is more particularly intended to treat conditions mediated by HDAC, such as cancers, in particular promyelocytic leukaemia, other diseases associated with abnormal cell proliferation, such as psoriasis, and also central and peripheral nervous system diseases and neurodegenerative diseases associated with an excitotoxicity, such as Huntington's disease, such as polyglutamine expansion diseases, Alzheimer disease, Parkinson disease, multiple sclerosis, neuronal ischemia and amyotrophic lateral sclerosis (ALS). The pharmaceutical composition is also more particularly useful in the treatment of fibrosis, e.g. liver fibrosis and liver chirrhosis.
The present invention also relates to the use of a compound as defined above, for the manufacture of a medicament for the treatment of conditions mediated by HDAC, such as cancers, in particular promyelocytic leukaemia, other diseases associated with abnormal cell proliferation, such as psoriasis, and also central and peripheral nervous system diseases and neurodegenerative diseases associated with an excitotoxicity, such as Huntington's disease, such as polyglutamine expansion diseases, Alzheimer disease, Parkinson disease, multiple sclerosis, neuronal ischemia and amyotrophic lateral sclerosis (ALS). It also deals with the use of a compound as defined above, for the manufacture of a medicament for the treatment of fibrosis, e.g. liver fibrosis and liver chirrhosis.
The present invention also includes methods of conditions mediated by HDAC, such as cancers, other diseases associated with abnormal cell proliferation, such as psoriasis, and also central and peripheral nervous system diseases and neurodegenerative diseases associated with an excitotoxicity as identified above, comprising the administration to a subject in need thereof of an effective amount of a compound as defined above.
As will be further disclosed in this application, the compounds according to this invention have strong HDAC inhibitory activity and are effective at reducing or arresting growth of proliferating cells such as tumour cells.